tbuckley/cabot-search huggingface dataset:
The impact of body mass index and serum albumin in patients with advanced-stage non-small cell lung cancer.
Authors: Andreas Bello, Neeharika Srivastava Makani
Journal: Journal of Clinical Oncology (2022)

e21037 Background: Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer diagnoses. Previous literature has evaluated associations between physical factors and outcomes in NSCLC. Throughout these studies, important physical factors that affect overall survival (OS) in NSCLC patients are body mass index (BMI) and serum albumin (SA) levels. In terms of BMI, previous research has come across the “obesity paradox.” That is, presenting an obese BMI serves as a protective role in patient survival. Hypoalbuminemia, defined as SA levels &lt; 3.5 g/dL, has been shown to have a significantly adverse effect on both early and late stage patients’ outcomes. Our study aims to analyze the role of BMI and SA in patients with advanced-stage NSCLC. Methods: This retrospective study includes 112 patients with stage III and stage IV NSCLC identified between January 1st, 2014 through December 31st, 2018. Categorical and continuous analyses (Pearson’s chi-square and Kruskal-Wallis test) were performed to analyze the associations between median OS, BMI, and SA. BMI subgroups are classified according to the Center for Disease Control guidelines. BMI and SA are calculated at time of diagnosis. OS is defined as the date of diagnosis until the date of death. Other notable confounders investigated include treatment modality, histology, and comorbidities. Results: Of the 112 patients, 57% of patients identified as male. The study population mean age was 73 years. The majority (88%) of patients identified as white. The median BMI was 26.1, with 26% of patients presenting as obese. The median SA level of the population was 3.8 g/dL, with 34% of patients presenting as hypoalbuminemic. Study population median OS was 0.734 years. Median OS for the obese BMI subgroup was 1.42 years, compared to 0.70, 0.71, and 0.42 years for overweight, normal, and underweight BMI, respectively. Kruskal-Wallis analyses confirm that patient BMI plays a significant difference in terms of OS, with a significant subgroup difference between patients with obese and underweight BMIs (p = 0.05). Regarding SA, both chi-square and Kruskal-Wallis tests confirm that at the time of diagnosis, patients with normal SA have a longer median OS compared to their hypoalbuminemic counterparts (median OS 1.29 years vs 0.32 years, respectively; OR = 6.72, 95% CI [2.48, 18.22], p &lt; 0.001). Conclusions: Our study reveals that an obese BMI plays a significant protective role regarding OS when evaluating prognostic outcomes between obese and underweight patients. Further, as SA levels are a known biomarker for nutritional status, our study highlights the importance of nutritional and educational optimization among healthcare professionals and patients alike prior to the diagnosis of malignancy. Future large prospective cohort studies are needed to analyze the efficacy of nutritional optimization, and further justify the “obesity paradox” and its underlying framework.
Discovery of potent, orally active KIF18A inhibitors targeting CIN-high cancer cells.
Authors: Rumin Zhang, Derek Cogan, Christina Eng, Aaron Phillips, Marysol Chu Carty, Tamar Feinberg, Akanksha Verma, Richard Tourdot, Albert Swiston, Sarah Bettigole, Scott Drutman, Michael Su
Journal: Journal of Clinical Oncology (2022)

e15046 Background: KIF18A is a kinesin assisting chromosome congression and alignment during mitosis. It is nonessential in normal, euploid cell division but essential for a subset of aneuploid cancer cells with high chromosomal instability (CIN-high). KIF18A knockdown in these cells leads to mitotic arrest, cytostasis and cell death. As a result, KIF18A is an attractive anticancer target. Methods: Volastra drug discovery efforts identified and validated KIF18A as a promising target using genetic knockdown and pharmacological inhibition with a tool compound. High-throughput screening identified an ATP-noncompetitive hit that was optimized for potency, selectivity, and pharmacokinetic properties. Breadth of efficacy studies against a panel of cancer cell lines were used to formulate responder hypotheses and aid in patient selection. Mechanistic profiling and cell fate determination upon KIF18A inhibition was used to identify target engagement and clinical response biomarkers. Results: Our lead candidates bind to KIF18A with sub-nM potency and exhibit long (̃2 days) drug-target residence time. They are ATP and microtubule uncompetitive. They are highly selective for KIF18A and have no known off-target effects on related kinesins and in an in vitro safety screen. They are orally bioavailable in preclinical species, well tolerated and demonstrate tumor regression in mouse xenograft models. In contrast to many agents that disrupt the mitotic machinery, KIF18A inhibition does not impact growth of proliferating normal cells. Breadth of efficacy studies performed on a large panel of human cancer cell lines reveal sensitivity to KIF18A inhibitors across multiple tumor types including high-grade serous ovarian, as well as subtypes of breast and lung cancer. Conclusions: Volastra’s research efforts have culminated in the discovery of orally active, highly potent, selective, and efficacious KIF18A inhibitors as development candidates.
MERLIN_001: A prospective registry study of a primary melanoma gene-signature to predict sentinel node (SN) status and determine its prognostic value for more accurate staging of patients with SN-negative melanoma.
Authors: Tina J. Hieken, Michael Earl Egger, Christina Vadala Angeles, Michael C. Lowe, Erin E. Burke, Edmund Bartlett, John Robert Hyngstrom, Vernon K. Sondak
Journal: Journal of Clinical Oncology (2022)

TPS9606 Background: For patients with cutaneous melanoma, sentinel lymph node biopsy (SLNB) provides important staging and prognostic information that guides surveillance and adjuvant systemic therapy decisions. At most centers, SLNB is indicated for patients with cutaneous melanoma with at least a 5% risk of having nodal metastases, typically melanomas ≥ 0.8 mm in thickness or thinner lesions with high-risk features such as elevated mitotic rate and/or ulceration. SLNB, generally involving a separate incision, does carry a small but measurable risk of complications including seroma, infection and rarely lymphedema, and most patients have negative sentinel lymph nodes. Currently, there is an unmet clinical need to identify patients who may safely forgo SLNB due to a low (&lt;5%) risk of nodal metastasis, who otherwise meet established criteria for SLNB. Previously, a model consisting of gene expression profile (GEP) of the primary tumor combined with clinicopathological features (CP) has been developed to identify melanoma patients with a low risk of having a positive SLNB. The model has also been validated in multiple retrospective studies. The aim of the MERLIN_001 registry study is to prospectively validate the CP-GEP model in an independent multicenter cohort of primary cutaneous melanoma patients who undergo SLNB for standard indications. Methods: In the next two years, a total of 10 centers across the US will enroll 2,340 patients with clinically node-negative cutaneous melanoma undergoing SLNB using current guideline indications and will follow these patients for 5 years (ClinicalTrials.gov identifier: NCT04759781). Enrollment of patients started in September 2021 and 242 patients have been enrolled as of February 1, 2022. FFPE material from the initial melanoma biopsy will be used to assess the GEP of the primary melanoma. The CP-GEP probability scores will be expressed as a binary classification (Low Risk or High Risk for nodal metastasis) and will be compared to SLN pathology. Performance metrics for CP-GEP will be evaluated and will include: Negative Predictive Value, Positive Predictive Value, Sensitivity and Specificity, and the corresponding 95% confidence intervals. Risk for nodal metastasis will be calculated for Low Risk and High Risk CP-GEP patients. Finally, the performance of CP-GEP to stratify patients according to risk of recurrence (local, regional, distant, death) will also be studied, since data will be collected for up to 5 yrs. Clinical trial information: NCT04759781.
Validation of the 31-gene expression profile test to stratify melanoma-specific survival in an unselected, prospectively tested cohort of patients with stage IIB-III cutaneous melanoma.
Authors: Young Hong, Sarah J. Kurley, Christine N. Bailey, Brian Martin, Matthew S. Goldberg, Valentina I. Petkov, Kyle R. Covington, Yousef Zakharia
Journal: Journal of Clinical Oncology (2022)

e21538 Background: Given recent FDA extended approval of Pembrolizumab for stage IIB-IIC cutaneous melanoma (CM) patients, it is critical to risk-stratify patients to balance potential benefits versus toxicities of adjuvant therapy. The 31-gene expression profile (31-GEP) is a validated test for CM for risk of recurrence or metastasis prognosis in patients with stage I-III CM. A low-risk (Class 1A) 31-GEP result is associated with lower recurrence risk and higher melanoma-specific survival than an intermediate (Class 1B/2A) or high-risk (Class 2B) result. To validate the 31-GEP’s ability to stratify patients’ risk in an unselected, prospectively tested cohort of therapy-eligible CM patients, we collaborated with the National Cancer Institute and the Surveillance, Epidemiology, and End Results (SEER) program. Methods: A linkage was conducted between SEER registries’ CM cases diagnosed 2012-2018, and 31-GEP tested patients between 2013-2020. A de-identified dataset was used for the analysis. Kaplan-Meier analysis with log-rank test was used to analyze patient melanoma-specific survival (MSS) in the overall cohort and the subset of patients with potential adjuvant therapy access: stage IIB-III melanoma (n = 615). Results: In the overall cohort of patients (N = 5,225), those with a 31-GEP Class 1A result had higher 3-year MSS than patients with a Class 2B result (99.7% vs. 90.4%, p &lt; 0.001). In multivariable Cox regression analysis, a Class 2B result was an independent significant predictor of MSS (HR = 5.71, p = 0.01), as were age (HR = 1.05, p &lt; 0.001), SLN positivity (HR = 2.42, p = 0.02), and T2b (HR = 8.29, p = 0.025) and T4b (HR = 11.99, p = 0.009) tumors. In the subset of patients with stage IIB-III melanoma, those with a 31-GEP Class 1A result had higher 3-year MSS (98.8% vs. 82.4%, p = 0.02) than patients with a Class 2B result. Patients with a Class 2B result had a five and a half times higher event rate than those with a Class 1A result for MSS (5.5% [21/382] vs. 1.0% [1/105]). Conclusions: In a large, unselected, prospectively tested cohort of patients with stage I-III CM, the 31-GEP stratified patient risk of dying from melanoma, validating previous studies. While the 31-GEP identified a subgroup (Class 1A) of traditionally high-risk patients (stage IIB-III CM) who had a &gt; 98% MSS over three years, it can also facilitate identifying patients who could warrant earlier adjuvant therapy with a higher 31-GEP class designation.
Tumor microenvironment (TME) dynamics following capecitabine/oxaliplatin (CapeOx) plus pembrolizumab in patients with advanced gastric cancer.
Authors: Minae An, Song-Yi Lee, Seung Tae Kim, Won Ki Kang, Jeeyun Lee
Journal: Journal of Clinical Oncology (2022)

4053 Background: Immune checkpoint inhibition (ICI) has made significant breakthroughs in several tumor types including gastric cancer (GC) in recent years. However, single-agent pembrolizumab demonstrated remarkable and durable response in MSI and EBV GC because they are immune-enriched types. Recently, we reported on-treatment remodeling of the TME during chemotherapy in MSS AGC ( Cancer Discov. 2021). We defined altered features including decreased tumor-associated macrophages (TAM), M1- macrophages repolarization and recruitment of NK cells, effector T cells. Methods: This phase 2, open-label, single-arm study was designed to assess the safety and efficacy of the CapeOx-pembrolizumab combination in advanced gastric cancer patients with HER2-negative. 38 patients were enrolled onto our CapeOx plus Pembrolizumab trial (NCT #04249739). All patients had MSS status with EBV-negative. Endoscopic biopsies were collected at baseline, after 1 cycle of chemotherapy alone and after 4 to 5 cycles of CapeOx + pembrolizumab to understand the impact of treatment to tumor TME. We performed coupling whole exome sequencing and whole transcriptome sequencing. Molecular features were extracted by exonic analysis. TME subtype was estimated by gene expression analysis. Results: Between 2020 and 2021, 38 patients were enrolled. There were 2 CR, 25 PR, 11 SD as best response.First, we found a number of somatic mutations (median 157.5, range 7-25,719) in pre-and on-treatment samples. Despite the creation and destruction of somatic mutation, we observed that ancestor mutations including TP53, MUC6 and APC previously reported in TCGA GC cohort, were preserved. At baseline (before chemotherapy), patients were classified to 5 immune-enriched (IE) subtye, 21 immune-depleted (D) subtype, ETC. Second, we observed a dynamic change following one cycle of CapeOx before the addition of pembrolizumab to chemotherapy. Nine (23.68%) out of thirty eight patients with immune-depleted or fibrotic pre-treatment TME became immune-favorable during treatment. Interestingly, seventeen (58.62%) out of twenty nine patients with immune-unfavorable pre-treatment TME became immune-favorable following CapeOx plus Pembrolizumab chemotherapy. Conclusions: This is the first study to demonstrate TME change during CapeOx plus pembrolizumab at molecular levels and will have clinically meaningful performance in patients with metastatic GC. Clinical trial information: NCT#04249739.
Naxitamab and granulocyte macrophage colony stimulating factor (GM-CSF) in combination with irinotecan and temozolomide in patients with high-risk neuroblastoma with primary refractory disease or in first relapse: An international, single-arm, multicenter phase 2 trial.
Authors: Godfrey Chi-Fung Chan, Charlotte Hindsberger, Anni Morsing, Steen Lisby
Journal: Journal of Clinical Oncology (2022)

TPS10061 Background: Neuroblastoma (NB) is the commonest extracranial solid tumor in children. At diagnosis, &gt; 50% have high-risk (HR) disease with poor prognosis despite intensive therapy; thus, there is a high unmet medical need. Naxitamab is an anti-GD2 monoclonal antibody indicated under accelerated approval in the US with GM-CSF for the treatment of relapsed/refractory HR NB in the bone and/or bone marrow in patients (pts) ≥1 year of age with a partial response, minor response, or stable disease to prior therapy. Irinotecan and temozolomide (IT) are commonly used salvage chemotherapies following failure of frontline therapy. The objective of this study is to investigate the efficacy and safety of naxitamab plus IT in pts with HR NB with primary refractory disease or first relapse. Methods: Trial 203 (NCT04560166) is an international, single-arm, multicenter phase 2 trial for HR NB patients ≥12 mo of age, with either evaluable primary refractory disease or first relapse following induction and consolidation therapy. The primary endpoint of the study is the centrally-assessed overall response rate (ORR) (complete [CR] or partial response) at or before completion of 4 cycles of treatment. Key secondary endpoints include ORR after 2 cycles of treatment, duration of response (DoR), CR rate, time to first subsequent therapy or death, progression-free survival (PFS), and overall survival (OS). 52 pts will be enrolled to provide 82% power to demonstrate that response rate is significantly higher than 20%. Key inclusion criteria are documented HR NB at time of diagnosis; received frontline induction/consolidation therapy; active disease despite previous aggressive chemotherapy; and measurable tumor (CT/MRI) that is either MIBG-avid/PET-positive or have MIBG scan with uptake at ≥1 site. Key exclusion criteria include prior treatment with duration ≤3 wks (chemotherapy), ≤6wks (autologous stem cell transplant or therapeutic 131 I-MIBG), ≤4wks (radiation therapy), or progressed while on anti-GD2; residual NB in the bone marrow only; and CNS/leptomeningeal disease in the prior 6 mo. In addition, there should not be &lt; 50% performance status per Lansky or Karnosky scale and life expectancy &lt; 6 mo. Pts will receive irinotecan 50 mg/m 2 /day IV and temozolomide 100 mg/m 2 /day orally (both on Days 1-5) in combination with naxitamab 2.25 mg/kg/day IV (Days 2, 4, 8 and 10) and GM-CSF 250 ug/m2/day sc (Days 6-10) in 21 days cycle. Response rates will be assessed using the 2-sided binomial test at the 5% significance level; DoR, PFS, and OS will be estimated using Kaplan-Meier analysis. Adverse events will be graded per CTCAE. Clinical trial information: NCT04560166.
Phase 2 trial of enoblituzumab plus retifanlimab or tebotelimab in first-line treatment of patients (pts) with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).
Authors: Grzegorz Obara, Jichao Sun, Deryk Loo, Gerry C. Bohac
Journal: Journal of Clinical Oncology (2022)

TPS6102 Background: Head and neck cancer accounts for ̃900,000 cases and over 400,000 annual deaths worldwide as of 2021. Pts with R/M SCCHN have a poor prognosis with median overall survival &lt;1 year. Programmed death (PD)-protein 1 (PD-1) and PD-ligand 1 (PD-L1) blockade has shown antitumor activity in advanced SCCHN. Enoblituzumab (MGA271) is an investigational monoclonal antibody (mAb) that binds B7-homolog 3 (B7-H3) with enhanced binding to the activating Fc gamma receptor CD16A, particularly the low-affinity allele CD16A-158. B7-H3 is overexpressed in many cancers, including SCCHN, but not in most normal tissues. Retifanlimab (MGA012, INCMGA00012) is an investigational anti-PD-1 mAb, blocking binding of PD-L1 or PD-ligand 2 (PD-L2) to PD-1. Tebotelimab (MGD013) is an investigational, Fc-bearing bispecific, tetravalent DART® molecule designed to bind PD-1 and lymphocyte activation gene 3, inhibiting their interaction with PD-L1 or PD-L2 and major histocompatibility complex class II. In vitro data suggest that both retifanlimab and tebotelimab have potential to sustain enoblituzumab-mediated immune activation and antitumor activity (Obara G, et al. Ann Oncol. 2021;32[suppl 5]:S814). Combination of enoblituzumab with retifanlimab or tebotelimab sustained the ability of natural killer cells and CD8+ T cells to produce interferon gamma upon restimulation. Both retifanlimab and tebotelimab enhanced enoblituzumab-dependent cytotoxicity targeting B7-H3–expressing tumor cells. In a phase 1/2 study, the combination of enoblituzumab with pembrolizumab was well tolerated (Aggarwal C, et al. J Immunother Cancer. 2022 [under review]). The overall response rate in anti-PD-1/PD-L1–naïve pts with SCCHN (post platinum) was 33% (6/18), including 1 confirmed complete and 5 confirmed partial responses, warranting further development of this combination in R/M SCCHN. Methods: This is an open-label, nonrandomized study in first-line treatment of pts with R/M SCCHN. Approximately 50 pts with PD-L1 combined positive score (CPS) ≥1 will receive enoblituzumab 15 mg/kg plus retifanlimab 375 mg and 30 pts with CPS &lt;1 will receive enoblituzumab 15 mg/kg plus tebotelimab 600 mg. Dosing is once every 3 weeks with tumor assessment at the end of Cycle 2 and every 3 cycles thereafter. Pts with no prior systemic therapy for R/M SCCHN are eligible. Pts who completed systemic therapy &gt;6 months before the study, if given as part of multimodal treatment for locally advanced disease, are eligible. In the tebotelimab cohort, safety data will be reviewed for dose-limiting toxicities through Cycle 2 Day 7 on the first 12 pts (2 mini cohorts of 6 pts each). All pts will be followed for survival after the last dose of study drug. The first pt was enrolled in March 2021, and 28 pts are on treatment as of January 19, 2022. Clinical trial information: NCT04634825.
Impact of acetaminophen on the efficacy of immunotherapy in patients with cancer.
Authors: Alban Bessede, Aurelien Marabelle, Jean-Philippe Guegan, Florent Peyraud, François-Xavier Danlos, Sophie Cousin, Nathalie Chaput, Mariella Spalato, Guilhem Roubaud, Mathilde Cabart, Mohamed Khettab, Assia Chaibi, Christophe Rey, Imane Nafia, François-Xavier Mahon, Jean-Charles Soria, Antoine Italiano
Journal: Journal of Clinical Oncology (2022)

12000 Background: Pain is the most common symptom experienced by patients with advanced cancer. Acetaminophen (APAP, commonly known as paracetamol) alone or in combination with a weak opioid, such as codeine or tramadol, is usually considered as the first-line strategy to manage mild-to-moderate pain in this setting. Although generally considered to be safe, several evidences suggest that APAP may have negative immunomodulatory effects. Randomized studies have shown that APAP use is associated with blunted vaccine immune responses. Given its potential to impair vaccine effectiveness, the World Health Organization stated in 2015 that administration of APAP before or at the time of vaccination is not recommended. This study aimed to assess APAP impact on efficacy of immunotherapy in patients with cancer. Methods: Exposure to APAP was assessed by plasma analysis and was correlated with clinical outcome in three independent cohorts of patients with advanced cancer who were treated with immune checkpoint blockers (ICB): the CheckMate 025 trial, n = 297 (NCT01668784, sponsor: Bristol Myers Squibb), the institutional biomarker program BIP n = 34 (NCT02534649, sponsor: Institut Bergonié, Bordeaux, France) and the institutional biomarker program PREMIS n = 297 (NCT03984318, sponsor: Gustave Roussy, Villejuif, France). APAP immunomodulatory effects were evaluated on a pre-clinical tumor model (MC38) and on human peripheral blood mononuclear cells (PBMCs) from healthy donors. Results: Detectable plasma APAP levels at treatment onset was associated with a significantly worse clinical outcome in ICB-treated cancer patients (HR for progression-free survival : 1.43, 95% CI 1.07–1.91, p = 0.015; HR for overall survival: 1.78 95% CI 1.18–2.68, p = 0.006), independently of other prognostic factors (age, performance status, number of previous lines of treatment, tumor type, number of metastatic sites, presence of liver metastases, LDH levels). APAP significantly reduced ICB efficacy in the pre-clinical MC38 model, as well as the production of PD1 blockade-related interferon-γ secretion by human PBMCs. Moreover, reduction of ICB efficacy in vivo was associated with significantly increased tumor infiltration by regulatory T cells (Tregs). Administration of APAP over 24 h induced a significant expansion of peripheral Tregs in healthy individuals. In addition, interleukin-10, a crucial mediator of Treg-induced immune suppression, was significantly upregulated upon treatment with ICB in cancer patients taking APAP. Conclusions: This study provides strong pre-clinical and clinical evidence of the role of APAP as a potential suppressor of antitumor immunity. Hence, APAP should be used with caution in patients treated with ICB.